Serotonin was discovered in the late 1940s and is present in both the peripheral and central nervous systems (Pytliak et al., Physiol. Res., 60 (2011) 15-25; Cowen et al., Psychopharmacology 21 3 (2011) 167-169). Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter of the indolalkylamine group that acts at synapses of nerve cells. Seven distinct families of serotonin receptors have been identified and at least 20 subpopulations have been cloned on the basis of sequence similarity, signal transduction coupling and pharmacological characteristics. The seven families of 5-HT receptor are 5-HT1, 5-HT2,5-HT35-HT4, 5-HT5, 5-HT6, and 5-HT7. Each of these receptors in turn has subfamilies or subpopulations. The 5-HT2 subtype family consists of 5-HT2A, 5-HT2B and 5-HT2C, all of which are G protein-coupled receptors. The signal transduction mechanism for all seven families has been studied. It is known that activation of 5-HT1 and 5-HT5 receptors causes a decrease in intracellular cAMP whereas activation of 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 results in an increase in intracellular inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The 5-HT pathways in the brain are important targets for drug development in the area of CNS disorders. Serotonin binds to its a G-protein coupled receptor and is involved in a wide variety of actions including cognition, mood, anxiety, attention, appetite, cardiovascular function, vasoconstriction, and sleep among others (Chen et al., ACS Medicinal Chemistry Letters 2 (2011) 929-932; Pytliak et al., supra).
There is evidence that demonstrates a role for the 5-HT2b receptor in a number of medical disorders, and therefore, 5-HT2b receptor activity modulators would have a beneficial effect on patients suffering from these disorders. The disorders in which 5-HT2b dysregulation plays a role and modulation of 5-HT2b receptor activity by a therapeutic agent would provide therapeutic relief include, but are not limited to, irritable bowel syndrome (WO 01/08668), disorders of gastric motility, dyspepsia, constipation, diarrhea, Crohn's disease, ulcerative colitis, gastroesophageal reflux disease, tachygastria, migraine, neurogenic pain (WO 97/44326), nociceptive pain (U.S. Pat. No. 5,958,934), anxiety (WO 97/44326), depression (WO 97/44326), benign prostatic hyperplasia (U.S. Pat. No. 5,952,331), sleep disorder (WO 97/44326), panic disorder, obsessive compulsive disorder, alcoholism, hypertension, anorexia nervosa, priapism (WO/97/44236), asthma, obstructive airway dysfunction, chronic obstructive pulmonary disease (COPD) (U.S. Pat. No. 5,952,331), incontinence, bladder dysfunction (WO 96/24351), and pulmonary hypertension (Launay, J. M. et al., Nature Medicine, 2002, 8, 10, 1129-1135).
There is a long felt need for new 5-HT2b receptor activity modulators that will provide therapeutic relief for patients suffering from diseases associated with dysregulation of 5-hydroxytryptamine receptor 2b activity. The present invention addresses the need to identify novel 5-HT2b modulators capable of treating disease associated with dysregulation of 5-hydroxytryptamine receptor 2b activity. The present invention addresses the need to develop new therapeutic agents for the treatment and prevention of irritable bowel syndrome, disorders of gastric motility, dyspepsia, constipation, diarrhea, Crohn's disease, ulcerative colitis, gastroesophageal reflux disease, tachygastria, migraine, neurogenic pain, nociceptive pain, anxiety, depression, benign prostatic hyperplasia, sleep disorder, panic disorder, obsessive compulsive disorder, alcoholism, hypertension, anorexia nervosa, priapism, asthma, obstructive airway dysfunction, chronic obstructive pulmonary disease (COPD), incontinence, bladder dysfunction, and pulmonary hypertension.